Model Study of the Hoppe Reaction Between Racemic Titanated Crotyl Carbamate and Enantiopure Aldehyde or γ-Lactol

Abstract

In our strategy for the total synthesis of tylonolide 2, aglycon of tylosin 1, and for the construction of the eastern part C1-C9, we planned to carry out a Hoppe homoaldolisation. In a model study, reaction was performed between racemic titanated crotyl carbamate (±)-3b and optically active aldehydes 6a-c. The expected syn-anti adducts 7a-c were obtained in good isolated yield together with the antianti isomer 8a-c. Interestingly, the γ−lactol 6d was also tested and delivered the syn-anti 7d compound in 70% isolated yield.In our synthetic approach to tylonolide 2, aglycon of the macrocyclic antibiotic tylosin 1 (scheme 1), 1 the western fragment C10-C15 was prepared earlier. 2 Stereospecific control at centers C14 and C15 was achieved using an extension of the Hoppe reaction. 3 Scheme 1The Hoppe reaction is an allylation of achiral aldehydes with crotyl N,N-diisopropyl carbamate 3, described as a "homoaldol reaction" by the authors. It involved the preparation of an optically active titanated crotyl carbamate 3b via the intermediate formation of an optically active lithio crotyl carbamate 3a by crystallization of its complex with (-)-sparteine [n-BuLi/(-)-sparteine, Ti(O i Pr) 4 ] (Scheme 2). The transition state was assumed to be a Zimmerman-Traxler cyclic model, 4 responsible for the formation of the Z-anti homoallylic alcohol 4. This reaction was earlier performed between the optically active allyltitanate 3b and achiral aldehydes, 3,4 and in a few cases between optically active partners, 5 or between an enantiopure aldehyde and racemic titanated crotyl carbamate. 6 Scheme 2In this paper, we report the results obtained in a study of the Hoppe homoaldolisation reaction using the racemic titanated (E)-crotyl carbamate 3b 3 and optically active butanals 6a-d with the desired C3 and C4 tylosin configurations.The racemic Hoppe's reagent 3b was prepared in the usual manner 7 and the aldehydes 6a-d from the known lactone 5 (Scheme 3). 8 Reaction with aldehyde 6a resulted in the formation of an unseparable mixture of syn-anti 7a and anti-anti 8a isomers in 75% yield and a 60:40 ratio (Scheme 4, table 1, entry 1). Scheme 3 Scheme 4When the same conditions were applied to the two silylated aldehydes 6b and 6c, reactions proceeded in better yields to deliver 7b,c and 8b,c derivatives (Table 1, entries 2 and 4). For the bis(triethylsilyl) aldehyde 6b the diastereoselectivity was unchanged but increased for the bulkier bis(triisopropylsilyl) aldehyde 6c (Table 1, entries 2 and 3). 7When 1 equivalent of crotyl carbamate 3 was used in the homoaldolisation of aldehyde 6c, yield decreased while the selectivity remained identical (Table 1, entry 4).

Stereo‐ und regiochemische Divergenz bei der Substitution eines lithiierten Alk‐1‐en‐3‐in‐2‐ylcarbamats – Synthese hoch enantiomerenangereicherter Vinylallene oder Alk‐3‐en‐5‐in‐1‐ole

“…Die 5S,6S,ZKonfiguration von 11 b wurde durch eine Röntgenstruktur-analyse aufgeklärt. [9,17] Zuvor haben wir, [18] wie auch andere Arbeitsgruppen, [19] demonstriert, dass a-Carbamoyloxyallyltitan-Verbindungen unter vollständigem Chiralitätstransfer mit Aldehyden über einen Zimmerman-Traxler-Übergangszustand [11] reagieren. Dadurch lässt sich die S-Konfiguration der Allyltitanverbindung 10 ableiten.…”

Anionic Cross‐Coupling Reaction of α‐Metallated Alkenyl Sulfoximines and Alkenyl Sulfoximines with Cuprates Featuring a 1,2‐Metal‐Ate Rearrangement of Sulfoximine‐Substituted Higher Order Alkenyl Cuprates and an α‐Metallation of Alkenyl Sulfoximines by Cuprates

“…In the Ni 0 -catalyzed ACCRs the sulfoximine group showed an exceptional ability to function as a nucleofuge. Because of a formal analogy between the nickel-ate complex (Z)-3 and the higher order (HO) cuprates (E)-7 and (Z)-7 (Scheme 3), we became interested to see 1) whether HO cuprates of this type can be generated from (Z)-2 and (E)-2, respectively, and organocuprates and 2) if they would undergo a stereoselective copper-based 1,2-MR [6,[11][12][13][14] to give the corresponding lower order (LO) cuprates (Z)-8 and (E)-8, respectively.…”

“…It had been shown that cuprates (E)-11, which were prepared from the lithiated or stannylated alkenyl carbamates (Z)-10 and LiCu(R 3 ) 2 , readily undergo a 1,2-MR with formation of the alkenyl cuprates (Z)-12, the trapping of which with electrophiles afforded (E)-9. [6,12] This route which can, however, only provide an access to the (E)-configured homoallyl alcohols (E)-9 is hampered by the limited stability of the a-lithioalkenyl carbamates (Z)-10, which suffer an elimination with formation of the corresponding alkynes even at low temperatures. [6,12] In contrast, the lithioalkenyl sulfoximines (Z)-2 and (E)-2 are stable towards elimination up to room temperature.…”

“…[6,12] This route which can, however, only provide an access to the (E)-configured homoallyl alcohols (E)-9 is hampered by the limited stability of the a-lithioalkenyl carbamates (Z)-10, which suffer an elimination with formation of the corresponding alkynes even at low temperatures. [6,12] In contrast, the lithioalkenyl sulfoximines (Z)-2 and (E)-2 are stable towards elimination up to room temperature. They are readily available through lithiation of the corresponding alkenyl sulfoximines (Z)-1 and (E)-1, respectively (cf.…”

Stereo‐ and Regiochemical Divergence in the Substitution of a Lithiated Alk‐1‐en‐3‐yn‐2‐yl Carbamate: Synthesis of Highly Enantioenriched Vinylallenes or Alk‐3‐en‐5‐yn‐1‐ols

“…The configuration of 11 b in the solid state could be determined by an X-ray analysis to be 5S,6S,Z. [9,17] Previously we [18] and others [19] demonstrated that chiral a-(carbamoyloxy)allyltitanium compounds react with chiral aldehydes with strict chirality transfer from the Zimmerman-Traxler transition state. Thus we deduce that the titanium intermediate 10 has S configuration, and 10 must be formed from (S)-8 with inversion of configuration.…”